New HIV-1 therapies that utilize novel antiviral mechanisms and exert a positive immunomodulatory effect are needed. Neurokinin-1 receptor (NK-1R) antagonists target the substance P (SP) receptor and have demonstrated antiviral and immunomodulatory effects. The NK-1R antagonists are a new therapeutic target with the potential to interrupt a pathway critical to HIV replication. The goal of this Integrated Preclinical/Clinical Program (IPCP) is to identify an NK-1R antagonist that is: (a) active as an anti-HIV agent through interaction with chemokine/cytokine receptors (Project 1); (b) specific for NK-1R interaction with CCR-5 (Project 2); (c) safe for use in SIV-infected non-human primates and provides proof of concept related to antiviral, immunomodulatory, and neurobehavioral effects (Project 3); and (d) safe in humans and has positive immunomodulatory effects (Project 4). We will demonstrate the safety, pharmacokinetics and therapeutic potential of an NK-1R antagonist (aprepitant or alternative) in SIV infection in the Rhesus macaque (Project 3). We will determine safety of an NK-1R antagonist (aprepitant or alternative) in relation to toxicity and effects on HIV viral load in a Phase I study of adults with HIV infection (Project 4). All projects contribute to understanding the basic virologic, molecular and cellular immunologic mechanisms of SP, NK-1R antagonists, and HIV/SIV infection. In a private sector partnership, with BBI Biotech Research Labs, Inc. (BBI) (Core B), synergy of candidate NK-1R antagonists with current antiretroviral drugs and in vitro antiviral activity against non-laboratory and resistant strains of HIV will be evaluated. An Administrative Core (Core A) and a Biostatistics and Pharmacology Core (Core C) will support the organizational study design, data management, and analysis needs of the program. Building on 10 years of HIV and SP collaborative research at The Children's Hospital of Philadelphia, this AIDS program project (investigators at the University of Pennsylvania Dept. of Pediatrics, Medicine and Psychiatry, PENN CFAR, PACTU, GCRC,Tulane National Primate Research Center, and BBI Biotech), will foster interactions across molecular, cellular, biopharmaceutical, and translational research, leading to novel HIV drug development.